CPSC Staff Statement on University of Cincinnati Report “Toxicity Review for Bis(2-ethylhexyl) Adipate (DEHA)”1 October 2018 The U.S. Consumer Product Safety Commission (CPSC) contracted with the University of Cincinnati to conduct toxicology assessments for six dialkyl o-phthalate (o-DAP) substitutes: acetyl tri-n-butyl citrate (ATBC); bis(2-ethylhexyl) adipate (DEHA); di-2-ethylhexyl terephthalate (DEHT); 1,2-cyclohexanedicarboxylic acid, dinonyl ester, branched and linear (DINX); trioctyltrimellitate (TOTM); and 2,2,4-trimethyl-1,3-pentanediol-diisobutyrate (TPIB). The reports will be used to inform staff’s assessment of products that may contain these compounds and is the first step in the risk assessment process. CPSC staff assesses a product’s potential health effects to consumers under the Federal Hazardous Substances Act (FHSA). The FHSA is risk-based. To be considered a “hazardous substance” under the FHSA, a consumer product must satisfy a two-part definition. First, it must be “toxic” under the FHSA, or present one of the other hazards enumerated in the statute. Second, it must have the potential to cause “substantial personal injury or substantial illness during or as a proximate result of any customary or reasonably foreseeable handling or use.” Therefore, exposure and risk must be considered in addition to toxicity when assessing potential hazards of products under the FHSA. The first step in the risk assessment process is hazard identification, which consists of a review of the available toxicity data for the chemical. If it is concluded that a substance may be “toxic”, then a quantitative assessment of exposure and risk is performed to evaluate whether a specified product may be considered a “hazardous substance”. The toxicity review for DEHA follows. 1 This statement was prepared by the CPSC staff, and the attached report was produced by the University of Cincinnati for CPSC staff. The statement and report have not been reviewed or approved by, and do not necessarily represent the views of, the Commission. TOXICITY REVIEW FOR BIS(2-ETHYLHEXYL)ADIPATE (DEHA) Contract No. CPSC-D-17-0001 Task Order No. 003 Prepared by: Risk Science Center Department of Environmental Health University of Cincinnati 160 Panzeca Way, Room G24 Cincinnati, OH 45267 Prepared for: Kent R. Carlson, Ph.D. U.S. Consumer Product Safety Commission 4330 East West Highway Bethesda, MD 20814 August 8, 2018 * This report was prepared for the Commission pursuant to contract CPSC-D-17-0001 It has not been reviewed or approved by, and may not necessarily reflect the views of, the Commission. This page intentionally left blank. 2 Table of Contents 1 Introduction ............................................................................................................................. 4 2 Physico-Chemical Characteristics ........................................................................................... 5 3 Manufacture, Supply, and Use ................................................................................................ 6 4 Toxicokinetics ......................................................................................................................... 8 5 Hazard Information ................................................................................................................ 10 5.1 Acute Single Dose Toxicity ........................................................................................... 10 5.1.1 Acute Oral Toxicity .................................................................................................... 10 5.1.2 Acute Dermal Toxicity ............................................................................................... 11 5.1.3 Acute Inhalation Toxicity ........................................................................................... 11 5.1.4 Irritation/Sensitization ................................................................................................ 11 5.2 Repeated Dose Toxicity ................................................................................................. 12 5.3 Chronic Toxicity/Carcinogenicity .................................................................................. 14 5.4 Reproductive Toxicity .................................................................................................... 17 5.5 Prenatal, Perinatal, and Postnatal Toxicity..................................................................... 20 5.6 Genotoxicity ................................................................................................................... 22 5.7 Mechanistic Studies........................................................................................................ 23 5.8 Mode of Action (MOA) ................................................................................................. 24 5.9 Lowest Hazard Endpoints by Organ System and Exposure Duration ........................... 25 5.10 Uncertainties and Data Gaps .......................................................................................... 26 6 Exposure ................................................................................................................................ 34 7 Discussion .............................................................................................................................. 36 7.1 Toxicity Under FHSA ........................................................................................................ 36 8 References ............................................................................................................................. 37 Appendix 1. Literature Search Terms Used …………………………………………..…………47 Appendix 2. Explanation of Physico-chemical Parameters .......................................................... 48 3 1 Introduction This report summarizes available data on the identity, physicochemical properties, manufacture, supply, use, toxicity, and exposure associated with bis(2-ethylhexyl)adipate (DEHA). It is an update of a previous contractor report to CPSC (Versar, 2010). Literature searches for physico-chemical, toxicological, exposure, and risk information were performed in November 2017 using the CAS number and synonyms (see Appendix 1 for the full list of search terms), and using the following databases: EPA SRS PUBMED RTECS TSCATS (included in TOXLINE) TOXNET databases, including o TOXLINE o CCRIS o DART/ETIC o GENE-TOX o HSDB Searches of the PubMed and Toxline databases covered all dates through the date of the search (November, 2017). However, studies dated up to 2007 were screened out of the library during the screening process using the Endnote files, as the current report supplements and updates a staff report prepared in 2010 (Versar, 2010). Other databases and websites were also used to identify additional key information, particularly authoritative reviews. Searches for authoritative reviews addressing general toxicity and physicochemical information were conducted with the following databases using the CAS number for DEHA and synonyms. These sites included: ANSES Information on Chemicals (https://www.anses.fr/en) ChemIDPlus (https://chem.nlm.nih.gov/chemidplus/) ECHA Information on Chemicals (https://echa.europa.eu/information-on-chemicals) EFSA (https://www.efsa.europa.eu/) EPA (https://www.epa.gov/) EPA chemistry dashboard (https://comptox.epa.gov/dashboard) EPA IRIS (https://www.epa.gov/iris) FDA (https://www.fda.gov/) Google 4 Health Canada (https://www.canada.ca/en/health-canada.html) IARC (https://www.iarc.fr/) INCHEM (http://www.inchem.org/) JECFA (http://www.who.int/foodsafety/areas_work/chemical-risks/jecfa/en/) NICNAS (https://www.nicnas.gov.au/) NTP (https://ntp.niehs.nih.gov/) OECD (http://www.oecd.org/) WHO (http://www.who.int/en/) Two new DEHA toxicology studies were identified in the literature searches. These were an evaluation of ovarian toxicity, female fertility and developmental toxicity in rats (Wato et al., 2009) and a developmental toxicity study in rabbits (Anonymous, 2014, as cited by ECHA, 2018). Other new studies that were found in the primary literature included studies on toxicokinetics, exposure and mechanism of action, as well as reviews. Several of the key toxicity studies were unpublished and not available as the primary studies. Therefore, these studies were evaluated based on authoritative reviews and data compilations, including SCENIHR (2008), Danish EPA (2010), OECD (2012), ANSES (2015), ECHA (2018), and Eastman Chemical (2010). Several additional review publications have been published since the previous CPSC assessment (Versar, 2010). Reviews and posted data from ECHA (2018) provided useful new information. 2 Physico-Chemical Characteristics DEHA is an ester of 2-ethylhexanol and adipic acid. Physical-chemical properties for this compound are highlighted in Table 1. Table 1: Physicochemical Properties and Identification Information for Di(2-ethylhexyl) Adipate Chemical Name Di(2-ethylhexyl) adipate Synonyms Hexanedioic acid, 1,6-bis(2-ethylhexyl) ester; Bis(2-ethylhexyl) hexanedioate; Di-(2-ethylhexyl) adipate; Dioctyl adipate; Hexanedioic acid, bis(2-ethylhexyl) ester; Adipic acid, bis(2- ethylhexyl) ester; Bis(2-ethylhexyl) adipate; DEHA; Di(2-ethylhexyl) adipate; Di(2-ethylhexyl) adipate; Di-2-ethylhexyl adipate; Hexanedioic acid, dioctyl ester; Octyl adipate CAS Number 103-23-1 Structure 5 (EPA Chemistry Dashboard) Chemical Formula C22H42O4 Molecular Weight 370.574 g/mol Physical State Liquid (MSDS Eastman